Abstract
BackgroundBiomarkers of early plaque progression are still elusive. Myeloid DAP12-associating lectin-1 (MDL-1), also called CLEC5A, is a C-type lectin receptor implicated in the progression of multiple acute and chronic inflammatory diseases. However, the relationship between its level and atherosclerosis is unknown. In this study, we aimed to investigate the correlation between macrophage MDL-1 expression and early atherosclerosis progression.MethodsImmunofluorescence staining, real-time PCR and western blot were performed to analyze MDL-1 expression in aorta or mice macrophages. The role of MDL-1 in macrophage survival was further investigated by adenovirus infection and TUNEL assay.ResultsSignificant MDL-1 expression was found in advanced human and apoE−/− mice atherosclerotic plaques, especially in lesional macrophages. In the model of atherosclerosis regression, we found MDL-1 expression was highly downregulated in lesional macrophages from ldlr−/− mouse regressive plaques, coincident with a reduction in lesional macrophage content and marker of M1 proinflammatory macrophages. Furthermore, we found MDL-1 was significantly expressed in inflammatory M1 subtype polarized bone marrow-derived macrophages. In vitro experiments, the level of MDL-1 was remarkably elevated in macrophages treated with pathophysiological drivers of plaque progression, such as oxidized low-density lipoprotein (ox-LDL) and hypoxia. Mechanistically, we demonstrated that MDL-1 overexpression notably promoted macrophage survival and decreased cleaved caspase-3 expression under ox-LDL stimulation, which suggested that it could maintain lesional macrophage survival and cause its accumulation.ConclusionsThis study firstly demonstrated that MDL-1 is mainly expressed in atherosclerotic lesional macrophages and increased macrophage MDL-1 expression is associated with early plaque progression and promotes macrophage survival.
Highlights
Biomarkers of early plaque progression are still elusive
We uncovered that Myeloid DAP12-associating lectin-1 (MDL-1) was mainly colocalized with CD68 in advanced human atherosclerotic plaques, which indicates MDL-1 is abundantly expressed in lesional macrophages (Fig. 1a)
Figure S1), which suggests MDL-1 associates with DAP12 and plays its role on advanced atherosclerotic lesion. Since these MDL-1 expressed lesional macrophages derived from peripheral blood circulating monocytes and MDL-1 was found to be expressed in monocytes, we detected MDL-1 expression in peripheral blood monocytes (PBMCs) from both coronary artery disease (CAD) patients and healthy volunteers
Summary
Myeloid DAP12-associating lectin-1 (MDL-1), called CLEC5A, is a C-type lectin receptor implicated in the progression of multiple acute and chronic inflammatory diseases. We aimed to investigate the correlation between macrophage MDL-1 expression and early atherosclerosis progression. Atherosclerosis is both a metabolic and an immunoinflammatory disease [1]. Studies demonstrated a strong expression of MDL-1 and DAP-12 in mature and differentiated monocytes/macrophages in contrast to undifferentiated bone marrow CD34+ stem cells or monocytes [11]. In this study, we aim to study the relationship between macrophage MDL-1 expression and early atherosclerosis progression and its role in macrophage apoptosis
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